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PubMed1996

Comparative cytotoxicity of 14 novel selenocysteine se-conjugates in rat renal proximal tubular cells.

Recently, Se-substituted selenocysteine conjugates were proposed as potential prodrugs to target biologically active selenol compounds to tissues containing high activities of cysteine conjugate beta-lyases, such as the kidneys. However, several selenium compounds are known to be relatively toxic compounds. In the present study, the cytotoxicity of 14 selenocysteine Se-conjugates was determined in freshly isolated rat renal proximal tubular cells (RPTC). The results of this study show that four selenocysteine Se-conjugates with alkyl substituents (methyl, ethyl, n-propyl, and n-butyl) did not cause significant cytotoxicity to RPTC up to concentrations of 500 microM after 90 min of incubation. Also, no effect was observed on mitochondrial functioning as indicated by the unaffected mitochondrial membrane potential (delta psi). Se-(i-Propyl)-selenocysteine, however, appeared to be a cytotoxic compound, causing time- and dose-dependent cytotoxicity, and caused a decrease of delta psi in remaining viable cells. Aminooxyacetic acid (AOAA) provided significant protection against cell death of Se-(i-propyl)-selenocysteine, pointing to involvement of cysteine conjugate beta-lyase. AOAA, however, did not prevent the decrease of delta psi. Differentially substituted Se-(phenyl)-L-selenocysteine and Se-(benzyl)-L-selenocysteine conjugates appeared to be cytotoxic to RPTC at a concentration of 200 microM, as indicated by increased cell death and a decreased delta psi in remaining viable cells. Within the Se-benzyl-series, Se-(4-methoxybenzyl)-L-selenocysteine was the most toxic conjugate, whereas Se-(4-chlorophenyl)-L-selenocysteine was the most toxic conjugate of the Se-phenyl compounds. The selenocysteine Se-conjugates with nonsubstituted phenyl and benzyl substituents were nontoxic at 200 microM, but caused significant cell death at a concentration of 500 microM. Preincubation with AOAA, an inhibitor of cysteine conjugate beta-lyase, provided only partial protection against the cytotoxicity of Se-(phenyl)-L-selenocysteine (500 microM) and Se-(4-methoxybenzyl)-L-selenocysteine (200 microM). AOAA did not protect against cytotoxicity of the other conjugates, suggesting direct effects of these compounds or involvement of alternative routes of bioactivation. This study demonstrates that cytotoxicity of selenocysteine Se-conjugates is strongly dependent on the nature of the Se-bound substituent. The nontoxic Se-(alkyl)-Se-conjugates may be promising candidates for further evaluation for chemopreventive activities.

Aminooxyacetic Acid↗
PubMed1995

Chemoprevention of cancer by organoselenium compounds.

A major research goal of our laboratories is the development of new organoselenium cancer chemopreventive agents with less toxicity compared to some of the historical selenium compounds, such as sodium selenite. Ideally, such agents would be employed to inhibit tumor development in different organs caused by a variety of chemical carcinogens, particularly those present in the human environment. A series of organoselenium compounds has been synthesized and evaluated for their chemopreventive efficacy in vivo. Parallel to these studies, short-term in vitro and in vivo assays were employed to understand the mechanism of action and to rapidly evaluate their efficacy in eventual long-term preclinical investigations. We demonstrated that one of the most effective of these organoselenium compounds, 1,4-phenylenebis(methylene)selenocyanate (p-XSC, Fig. 1), is capable of inhibiting tumors in the mammary glands, colon, and lung of laboratory animals. Dietary p-XSC inhibited mammary tumor development induced by 7,12-dimethylbenz(a)anthracene (DMBA) during both the initiation and post-initiation phases of carcinogenesis in female CD rats. p-XSC inhibited DMBA-DNA adduct formation in the mammary glands. In collaboration with other laboratories, we demonstrated that p-XSC inhibited thymidine kinase in mammary tumor cell lines derived from both humans and rats. Employing mammary carcinoma cell lines, p-XSC was also shown to inhibit cell growth and induce a dose-dependent increase in cell death by apoptosis. In these assays p-XSC appears superior to selenite and to its sulfur analog, 1,4-phenylenebis(methylene)thiocyanate. Dietary p-XSC decreased colon tumor induction by azoxymethane in F344 rats during both phases of carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Selenium speciation in human body fluids.

Selenium consumed by humans in foods and in supplements exists in a number of different organic and inorganic forms including selenomethionine, selenocysteine, selenate and selenite. Animal and human studies have established that the bioavailability of the selenium depends upon the chemical form, which also influences the distribution of selenium in the body. These studies have included urinary excretion of selenium following ingestion of different forms of selenium and the response of tissue selenium concentrations and activities of functional selenoproteins to these selenium compounds. Selenomethionine is retained in tissue proteins to a greater extent than selenocysteine and the inorganic forms, but the selenium is not necessarily immediately available for functional selenoproteins. A number of other factors besides chemical form may also influence the bioavailability and distribution of selenium, including other dietary components, selenium status, physiological status and species. Knowledge of these factors and of speciation of selenium in foods, tissues and functional selenoproteins is important for the accurate assessment of selenium status. Speciation of selenium also has implications with respect to the determination of selenium requirements and to the investigation of relationships between selenium status and health and disease.

Biological Availability↗
PubMedDate not supplied

Effects of dietary selenium on sperm motility in healthy men.

A deficiency of dietary selenium leads to immotile, deformed sperm and infertility in rats, whereas supplementation of the diet with selenium compounds has been associated with both beneficial and deleterious effects on sperm function, depending on the chemical form of selenium. We conducted a randomized, controlled, and blinded intervention study on the effects of selenium in food on semen quality. Eleven healthy men were fed a controlled diet of foods naturally high or low in selenium for 120 days while confined in a metabolic research unit. Dietary selenium was 47 microg/d for the first 21 days, then either 13 microg/d or 297 microg/d for 99 days, resulting in significant changes in selenium concentrations in blood and semen. Seminal plasma selenium concentration increased 50% with high selenium and decreased 40% with low selenium. The fraction of motile sperm in the high-selenium group decreased by 32% by week 13 and ended 18% lower than baseline. Selenium concentrations changed in seminal plasma but not in sperm, and serum androgen concentrations were unchanged in both groups, indicating this effect was neither androgen dependent nor caused by a change in the selenium supply to the testes. Serum triiodothyronine decreased and thyroid-stimulating hormone increased in the high-selenium group, suggesting that altered thyroid hormone metabolism may have affected sperm motility. Although this decrease in sperm motility does not necessarily predict decreased fertility, the increasing frequency of selenium supplementation in the healthy population suggests the need for larger studies to more fully assess this potential side effect.

Dietary Supplements↗
PubMedDate not supplied

[Biochemical role of selenium].

The molecular mechanisms of selenium regulation of biochemical functions in animal and human tissues are presented in review. It is shown, that in spite of high toxicity selenium is an essential nutrient for people and animals. Taking into account deficit of this microelement in fodder it is necessary to use the selenium compounds in rations of domestic animals and poultry. The study of properties and characteristics of selenoproteins is important in discovering selenium role in regulation of cellular growth processes, the protective effect of this element in prevention of toxic action of heavy metals, xenobiotics and bacterial toxins on organism and anticarcinogenic effect of selenium.

Animals↗
PubMed1983

Mode of in vitro interaction of mercuric mercury with selenite to form high-molecular weight substance in rabbit blood.

Mode of interaction of mercuric mercury and selenite in rabbit blood was investigated in vitro. After the incubation of rabbit blood with 10(-5) M each of 203HgCl2 and Na2(75)SeO3, the amounts of both 203Hg and 75Se incorporated into erythrocytes were markedly larger than the case where the blood was treated separately with one of these compounds. Most of 203Hg and 75Se distributed into plasma and erythrocytes were found in high-molecular weight substance(s) (HMWS) fractionated by gel filtration at a molar ratio of 1:1. The 203Hg and 75Se in HMWS found in plasma and erythrocytes were hardly diffusable through the erythrocytes membrane. The formation of the HMWS containing mercury and selenium was observed in stroma-free hemolysate incubated with mercuric chloride and selenite, but not in plasma. Addition of reduced glutathione (GSH) to the plasma, however, gave the HMWS as reaction products containing equimolar amounts of mercury and selenium. Further the binding properties of selenium to proteins were studied in the plasma incubated with selenodiglutathione (GSSeSG) or with selenite in the presence of GSH. The results indicated that GSH, a cellular component, is essential for the formation of an active selenium compound from selenite and that the interaction of mercuric mercury and selenite in plasma in the presence of GSH may occur through the other mechanism than the formation of GSSeSG.

Animals↗
PubMed1991

Selenium: inhibition of microtubule formation and interaction with tubulin.

We have studied the interaction of Na2SeO3 with microtubule proteins and tubulin. This selenium compound inhibits the polymerization of MTP (half-inhibition occurred for Na2SeO3 10 microM), and to a lesser that of tubulin. This effect of selenite is related to the formation of disulfide bridges between tubulin sulfhydryl groups, inducing a conformational change of the protein. This is corroborated by the modified binding of colchicine and vinblastine in presence of selenium. The selenite inhibitory concentrations are similar to the toxic blood levels of selenium (40 microM).

Animals↗
PubMedDate not supplied

Selenium. Preclinical studies of anticancer therapeutic potential.

Selenium is a trace element that is essential to the human diet. Deficiency states have been described in both animals and humans. In addition, selenium compounds have demonstrated toxicity in humans, as well as in human tissues in culture. As early as 1956, one form of selenium was used as an antineoplastic agent in humans with some demonstrated activity. Recently, evidence in both tumor-bearing animals and human tumor cells in culture have confirmed an antitumor effect of potential clinical benefit. The mechanism of this cytoxic effect appears, at least in part, to relate to the property of some forms of selenium to oxidize critical sulfhydral groups in the cell. Evidence for this, and the resulting implications for the use of selenium in anticancer treatment, is presented in this manuscript.

Antineoplastic Agents↗
PubMed2002

Modern trends in the speciation of selenium by hyphenated techniques.

The complexity of selenium speciation in the environment and in living organisms results in broad analytical challenges. The importance of the selective determination of the particular species of this element, to understand its metabolism and biological significance in clinical chemistry, biology, toxicology, and nutrition, calls for state-of-the-art analytical techniques. In this paper hyphenated techniques are evaluated with particular emphasis on interfaced separation with element-selective detection and identification of the selenium compounds detected.

Chromatography, Gas↗
PubMed2002

Selenomethionine regulation of p53 by a ref1-dependent redox mechanism.

The cancer chemopreventive properties of selenium compounds are well documented, yet little is known of the mechanism(s) by which these agents inhibit carcinogenesis. We show that selenium in the form of selenomethionine (SeMet) can activate the p53 tumor suppressor protein by a redox mechanism that requires the redox factor Ref1. Assays to measure direct reduction/oxidation of p53 showed a SeMet-dependent response that was blocked by a dominant-negative Ref1. By using a peptide containing only p53 cysteine residues 275 and 277, we demonstrate the importance of these residues in the SeMet-induced response. SeMet induced sequence-specific DNA binding and transactivation by p53. Finally, cellular responses to SeMet were determined in mouse embryo fibroblasts wild-type or null for p53 genes. The evidence suggests that the DNA repair branch of the p53 pathway was activated. The central relevance of DNA repair to cancer prevention is discussed.

Animals↗
PubMedDate not supplied

Report on the 1986 A.S.P.E.N. Research Workshop on selenium in clinical nutrition.

Selenium in human nutrition was the theme of the 1986 Research Workshop of the American Society for Parenteral and Enteral Nutrition. At the workshop, evidence for the nutritional essentiality of selenium to humans was reviewed, and it was concluded that Keshan disease, the cardiomyopathy of children and young women described in China, is now firmly linked to selenium deficiency, although other factors may be involved. Selenium metabolism and techniques for assessing selenium status also received attention at the workshop. A measurement of blood selenium levels was accepted, in general, as a valid technique for assessing selenium status in individuals with relatively constant selenium intakes. Clinical practitioners at the workshop reported that some of their total parenteral nutrition patients not receiving selenium presented biochemical evidence of selenium deficiency, but no characteristic clinical syndrome due to selenium deficiency has yet been observed in such patients. The workshop attendees acknowledged the need for an official guideline for selenium use in total parenteral nutrition, but were unable to develop a consensus regarding such a guideline. However, the workshop agreed that any guideline established in the future should specify the type of patients to be supplemented, the dose of selenium to be administered, and the selenium compound to be used. Until that time, the physician supervising the therapy must assume responsibility both for determining the need for selenium supplementation, and for the administration of the supplemental selenium.

Adult↗
PubMed1984

Comparison of cytotoxicity of mercury-selenium and mercury compounds on cultured cells.

In vitro effects of mercury-selenium (Hg-Se) compounds, as compared with their original mercury compounds, against growth and viability of HeLa cells were studied. A water-soluble, ethanol-insoluble black complex (GX) formed from HgCl2, Na2SeO3 and GSH was less toxic than HgCl2, but the cytotoxicity of bis(methylmercuric) selenide (BMS) seemed to be similar to that of methylmercury. This may be due to the instability of BMS; i.e., there is a possibility that BMS decomposed to methylmercury and selenium under our culture conditions.

Cell Survival↗
PubMed1982

Selenocysteine lyase, a novel enzyme that specifically acts on selenocysteine. Mammalian distribution and purification and properties of pig liver enzyme.

We have found a novel enzyme that exclusively decomposes L-selenocysteine into L-alanine and H2Se in various mammalian tissues, and have named it selenocysteine lyase. The enzyme from pig liver has been purified to homogeneity. It has a molecular weight of approximately 85,000, and contains pyridoxal 5'-phosphate as a coenzyme. Its maximum reactivity is at about pH 9.0. Balance studies showed that 1 mol of selenocysteine is converted to equimolar amounts of alanine and H2Se. The following amino acids are insert: L-cysteine, L-serine, L-cysteine sulfinate, selenocysteamine, Se-ethyl-DL-selenocysteine, and L-selenohomocysteine. L-Cysteine (Ki, 1.0 mM) competes with L-selenocysteine (Km, 0.83 mM) to inhibit the enzyme reaction. The enzyme is the first proven enzyme that specifically acts on selenium compounds.

Animals↗
PubMed2000

A method for measuring disulfide reduction by cultured mammalian cells: relative contributions of glutathione-dependent and glutathione-independent mechanisms.

A method is described for measuring bioreduction of hydroxyethyl disulfide (HEDS) or alpha-lipoate by human A549 lung, MCF7 mammary, and DU145 prostate carcinomas as well as rodent tumor cells in vitro. Reduction of HEDS or alpha-lipoate was measured by removing aliquots of the glucose-containing media and measuring the reduced thiol with DTNB (Ellman's reagent). Addition of DTNB to cells followed by disulfide addition directly measures the formation of newly reduced thiol. A549 cells exhibit the highest capacity to reduce alpha-lipoate, while Q7 rat hepatoma cells show the highest rate of HEDS reduction. Millimolar quantities of reduced thiol are produced for both substrates. Oxidized dithiothreitol and cystamine were reduced to a lesser degree. DTNB, glutathione disulfide, and cystine were only marginally reduced by the cell cultures. Glucose-6-phosphate deficient CHO cells (E89) do not reduce alpha-lipoate and reduce HEDS at a much slower rate compared to wild-type CHO-K1 cells. Depletion of glutathione prevents the reduction of HEDS. The depletion of glutathione inhibited reduction of alpha-lipoate by 25% and HEDS by 50% in A549 cells, while GSH depletion did not inhibit alpha-lipoate reduction in Q7 cells but completely blocked HEDS reduction. These data suggest that the relative participation of the thioltransferase (glutaredoxin) and thioredoxin systems in overall cellular disulfide reduction is cell line specific. The effects of various inhibitors of the thiol-disulfide oxidoreductase enzymes (1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), arsenite, and phenylarsine oxide) support this conclusion.

Animals↗
PubMed1985

Effect of ascorbic acid supplementation on selenium bioavailability in humans.

The study was designed to investigate the effect of supplemental ascorbic acid on the bioavailability of selenium (Se) in humans by using plasma Se levels and plasma glutathione peroxidase (GSH-Px) activity as indicators of the body Se status. Three groups of female university students were supplemented for 4 weeks with either 50 micrograms sodium selenate, 50 micrograms sodium selenate together with 200 mg ascorbic acid, or with 200 mg ascorbic acid three times daily during meals. Plasma Se levels increased significantly (P less than 0.01) in all three groups regardless of the type of supplementation. The increase was highest in the group having both Se and ascorbic acid and smallest in the group receiving only ascorbic acid. The changes in plasma GSH-Px activities reflected those in plasma Se, but the increases were smaller (P less than 0.05). These results suggest that supplemental ascorbic acid may have a beneficial effect on the bioavailability of the natural Se in foods. However, ascorbic acid did not seem to affect the availability of the supplemental sodium selenate. Therefore, the effect of ascorbic acid on the bioavailability of selenium may vary depending on the ingested selenium compound.

Adult↗
PubMed2002

Intracellular glutathione is a cofactor in methylseleninic acid-induced apoptotic cell death of human hepatoma HEPG(2) cells.

Selenium is a widely studied dietary anticancer agent. Among various selenium compounds, the methylated forms appear to be particularly effective in cancer prevention. Intracellular glutathione (GSH) is known to be involved in the metabolism of many methylated forms of selenium. In this study, we investigated the role of intracellular GSH in methylseleninic acid (MSeA)-induced apoptosis in human hepatoma (HepG(2)) cells. MSeA was shown to deplete intracellular GSH rapidly, preceding the typical apoptotic changes such as DNA fragmentation as measured by the TUNEL assay. When the intracellular GSH concentration was enhanced using N-acetylcysteiene (NAC) (a GSH synthesis precursor) and decreased using buthionine sufoxamine (BSO) (a GSH synthesis inhibitor), NAC markedly augmented MSeA-induced apoptosis, while BSO significantly inhibited MSeA-induced apoptosis. Different from the effect of sodium selenite, there was no measurable superoxide radical level in MSeA-treated cells. These observations suggest that intracellular GSH mainly acts as a cofactor to facilitate MSeA-induced apoptosis, while its antioxidant function becomes largely irrelevant. It is thus postulated that some cancer cells, such as liver cancer cells with higher level of intracellular GSH, would be more susceptible to MSeA cytotoxicity.

Anticarcinogenic Agents↗
PubMed2002

Reactive oxygen species from mitochondria mediate SW480 cells apoptosis induced by Na2SeO3.

A number of selenium compounds have been found to inhibit tumorigenesis in a variety of animal and cell models. In order to explore the molecular mechanism involved in the anticarcinogenesis activity of selenium, we examined the effects of sodium selenite on cell viabilty, generation of reactive oxygen species (ROS), and mitochondrial transmembrane potential (delta(psi)m) in human colonic carcinoma cells SW480. The result from MTT test showed that sodium selenite reduced cell viability. Morophologic and flow cytometric results indicated that Na2SeO3 induced the apoptosis of SW480 cells. Na2SeO3 increased the generation of intracellular ROS, whereas BAPTA-AM, rotenone, and NaCN completely inhibited the increase of ROS induced by Na2SeO3. Na2SeO3 also caused the disruption of delta(psi)m. The intracellular ROS increase and apoptosis induced by Na2SeO3 were significantly decreased by superoxide dismutase (SOD), catalase. These data suggest that the ROS mediate apoptosis induced by Na2SeO3 and mitochondria may be a major source of Na2SeO3-induced ROS.

Apoptosis↗